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RANKL-mediated reactive oxygen species pathway that induces long lasting Ca2+ oscillations essential for osteoclastogenesis

Title
RANKL-mediated reactive oxygen species pathway that induces long lasting Ca2+ oscillations essential for osteoclastogenesis
Authors
Kim M.S.Yang Y.-M.Son A.Tian Y.S.Lee S.-I.Kang S.W.Muallem S.Shin D.M.
Ewha Authors
강상원
SCOPUS Author ID
강상원scopus
Issue Date
2010
Journal Title
Journal of Biological Chemistry
ISSN
0021-9258JCR Link
Citation
vol. 285, no. 10, pp. 6913 - 6921
Indexed
SCI; SCIE; SCOPUS WOS scopus
Abstract
RANKL (receptor activator of NF-κB ligand) induces osteoclastogenesis by activating multiple signaling pathways in osteoclast precursor cells, chief among which is induction of long lasting oscillations in the intracellular concentration of Ca2+ ([Ca2+]i). The [Ca 2+]i oscillations activate calcineurin, which activates the transcription factor NFATc1. The pathway by which RANKL induces [Ca 2+]i oscillations and osteoclastogenesis is poorly understood. Here we report the discovery of a novel pathway induced by RANKL to cause a long lasting increase in reactive oxygen species (ROS) and [Ca 2+]i oscillations that is essential for differentiation of bone marrow-derived monocytes into osteoclasts. The pathway includes RANKL-mediated stimulation of Rac1 to generate ROS, which stimulate phospholipase Cγ1 to evoke [Ca2+]i oscillations by stimulating Ca2+ release from the inositol 1,4,5-trisphosphate pool and STIM1-regulated Ca2+ influx. Induction and activation of the pathway is observed only after 24-h stimulation with RANKL and lasts for at least 3 days. The physiological role of the pathway is demonstrated in mice with deletion of the Peroxiredoxin II gene and results in a mark increase is ROS and, consequently, a decrease in bone density. Moreover, bone marrow-derived monocytes in PrxII-/- primary culture show increased ROS and spontaneous [Ca2+]i oscillations. These findings identify the primary RANKL-stimulated pathway to trigger the late stages of osteoclastogenesis and regulate bone resorption. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.
DOI
10.1074/jbc.M109.051557
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자연과학대학 > 생명과학전공 > Journal papers
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